We have previously shown that oral conjugated equine estrogen (CEE) reduces plasminogen activator inhibitor (PAI-1) levels in postmenopausal women, an effect associated with proportionate increases in degradation products of fibrin. However, oral estrogen reduces low-density lipoprotein cholesterol (LDL-C) levels that may account for PAI-1 effects, as oxidized LDL stimulates endothelial synthesis of PAI-1 in cell culture experiments. To assess the importance of LDL on PAI-1, we administered CEE .625 mg, simvastatin 10 mg, or the combination daily for 6 weeks each to 25 hypercholesterolemic (LDL=165+/-37 mg/dL; mean+/- SD) postmenopausal women in a randomized, double-blind, double-crossover study. Data=% delta from respective pretreatment values. CEE Simvastatin CEE/Simvastatin LDL-C -11+/-11* -25+/-14*+ -32+/-15*+ ApoB -9+/-8* -23+/-10*+ -27+/-13*+ PAI-1 -25+/-45** +22+/-83 -16+/-51*** *=P<.001, **=P<.005, ***=P<.02 vs. respective pretreatment baseline values; +=P<.005 vs. CEE. Only therapy including CEE reduced PAI-1 antigen levels, despite a greater effect of simvastatin on reduction in LDL-C and apolipoprotein B levels. Further, there was no synergism of combined CEE and simvastatin therapy on PAI-1 levels. These data suggest that estrogen reduces PAI-1 levels independent of changes in LDL. This primary effect of CEE on fibrinolytic potential may favor its use in hypercholesterolemic postmenopausal women, even if they are already on lipid-lowering therapy.